Stopping epileptogenesis dead in its trks.

Commentary Kinases are ubiquitous enzymes that regulate cellular function by the simple act of transferring a phosphate group to a serine, threonine, or tyrosine residue on a protein substrate. Long a subject of interest at a basic science level, kinases have more recently become the focus of drug development for a number of diseases. Imatinib, an inhibitor of the tyrosine kinase abl, revolutionized the treatment of chronic myelogenous leukemia and became a blockbuster drug. Numerous other new drugs—mostly aimed at oncologic applications—have followed, and drug development against kinases now represents a major focus of pharmaceutical companies (1). Interest in kinases and phosphorylation signaling is spreading to the epilepsy field as well. The recognition that the kinase mammalian target of rapamycin (mTOR) is hyperactivated in tuberous sclerosis (TS) has stimulated multiple investigations, demonstrating that pharmacologic mTOR inhibition is an effective antiepileptic treatment in humans with TS (2). Several investigators have taken this a step further, testing whether mTOR inhibition might be effective in animal models of acquired rather than genetic epilepsy. While the results of these studies are not yet conclusive, there is evidence that mTOR inhibition may exert an antiepileptic action and possibly even an antiepileptogenic effect—that is, delaying or preventing the development of epilepsy after a neural insult (3, 4). However, there is no a priori reason that mTOR should be the only kinase involved in the development of acquired epilepsy ; likely, multiple phosphorylation signaling pathways are activated following a neural insult. The tyrosine kinase TrkB is the latest candidate effector of epileptogenesis. As the current study by Liu et al. demonstrates, TrkB appears to be a critical mediator of epileptogenesis in at least one model of acquired epilepsy. TrkB is the receptor for brain-derived neurotrophic factor (BDNF), a molecule that had been widely hypothesized to mediate epileptogenesis. However, the investigators of the present study had previously demonstrated that genetic deletion of BDNF only modestly impaired development of kindling, while deletion of TrkB virtually abolished kindling (5). This focused attention away from BDNF and towards TrkB as a potential mediator of epileptogenesis in animal models. It might be argued that kindling is not a sufficiently robust model from which to draw conclusions about epileptogen-esis given (in most cases) a lack of spontaneous seizures in kindled animals. The current study takes this issue head-on by using kainic acid (KA) injected into the amygdala to produce chronically epileptic mice. The …